The invention relates to novel substituted N-benzo(thia/oxa)zine-2-yl-1-arylalkyloxyalkyl-4-piperidinamines of formula I: 
(in which the radicals are as defined in the invention), to their preparation and to their therapeutic application.
In a recent patent from the Applicant (WO 97/05134), N-alkyl-N-[1-(xcfx89-aryloxyalkyl)-4-piperid]-4H-3,1-benzothiazin-2-amines of therapeutic value, particularly in the treatment of myocardial ischemia, were mentioned.
In the course of the structure/activity study, it was decided to increase the space between the phenyl radical and the oxygen via the introduction of an alkylene radical to measure the impact on the cytoprotective activity of such a structural modification. The substitution of the piperidine nitrogen with an arylalkyloxyalkyl radical instead of an aryloxyalkyl radical allowed the identification of a new class of compounds which showed activity superior to that of the compounds of the base series. The compounds of this novel series form the subject of the present invention.
The molecules of the present invention belong to the class of substituted N-alkyl-N-[1-(xcfx89-(arylalkyloxy)alkyl]-4-piperidyl]-4H-3,1-benzo[thia/oxa)zine-2-amines and are of formula I: 
in which:
X represents an oxygen or sulfur atom
Y represents either
a branched or unbranched alkylene radical containing from 2 to 6 carbon atoms or
a xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94 radical
R represents a hydrogen, a saturated or unsaturated, branched or unbranched alkyl radical containing from 1 to 7 carbon atoms,
R1 to R6, which may be identical or different, represent:
a hydrogen,
a branched or unbranched, saturated or unsaturated alkyl containing from 1 to 5 carbon atoms,
a branched or unbranched, saturated or unsaturated alkyloxy containing from 1 to 5 carbon atoms,
a halo group,
a nitro group,
a hydroxyl group,
an acyl or acyloxy group containing from 2 to 3 carbon atoms,
a dialkylamino group containing from 1 to 5 carbon atoms,
a trifluoromethyl or trifluoromethoxy group,
n is an integer which may range from 1 to 6 inclusive.
The present invention also includes the therapeutically acceptable mineral or organic salts of the compounds of formula I and the possible hydrates thereof. The invention also relates to processes for preparing the derivatives claimed, and also to their application as medicinal products. The molecules of the present invention of formula I have noteworthy cytoprotective properties, the activity of which is superior to that of the base family claimed in patent WO 97/05134.
The compounds of formula I may be prepared according to two main routes, ending either with N-alkylation or with heterocyclization.
a) When Y represents an alkylene, the compounds of formula I are generally prepared by condensing an arylalkyloxyalkyl halide or mesylate of formula III with an N-(4-piperidyl)-4H-3,1-benzothiazin-2-amine II in the presence of an organic or mineral base in an organic solvent according to the reaction: 
in which Z=Cl, Br, I, or MeSO3.
The method for preparing ethers III varies according to the length of the carbon chain in the divalent alkylene group Y.
When the base chain Y contains more than 3 carbon atoms, the ether is prepared by condensing an excess of the 1,xcfx89-dibromoalkane V with the corresponding alcohol IV in a strong basic medium using a phase-transfer catalyst such as tetrabutylammonium bisulfate according to A. W. Burgstahler et al. (J. Org. Chem., 1977, 42, 566-8) according to the reaction: 
When Y represents a trimethylene, the preceding reaction applied to 1,3-dibromopropane gives the expected derivative III in a low yield (10 to 30%) and allylic ether is above all formed. In this case, it is preferred to use 1-bromo-3-chloropropane to prepare the chloro derivative III (Z=Cl) in a yield of about 50 to 60%.
When Y represents an ethylene, the preceding reaction cannot be performed, and it is preferable to condense the starting alcohol IV with ethylene carbonate in the presence of sodium hydride according to Van den Brock L. A. G., Vermaas D. J. et al. (Recueil Trav. Chim. Pay-Bas, 1994, 113, 507-516). In this case, an intermediate (2-arylalkoxy) ethanol VI is obtained, which may be activated in the form of mesylate III (Z=MeSO3xe2x80x94) after treatment with mesyl chloride according to the reaction: 
b) When Y represents a xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94 radical, the compounds I of the present invention are similarly prepared, but using an arylalkyloxymethoxy epoxide VII as alkylating agent, according to the reaction: 
The glycidyl ethers VII are prepared by condensing epichlorohydrin with the corresponding alcohols IV by phase transfer catalysis by means of the process already described (Mouzin G. et al. Synthesis, 1983, 117-119) according to the reaction: 
When the starting alcohols IV are not commercially available, they are obtained from the corresponding ethyl or methyl esters VIII by reduction in the presence of aluminohydride: 
The synthesis of the heterocycle III has already been described in the application of the base series WO 97/05314.
The compounds I may be prepared by final cyclization using two types of activation of the amines attached to the heterocycle.
a) In a first case, the aromatic amine may be activated in the form of o-bromomethyl phenyl isothiocyanate IX as described in patent WO 97/05314, by reaction with the suitably substituted aminopiperidine X according to: 
b) The activation may also derive from the amine borne by the piperidine nucleus. The activation may be produced in two ways depending on the nature of the radical R and always takes places in two steps:
If R is hydrogen, the amine X may be activated in the form of iso(thio)cyanate XI by reaction with triphosgene or (thio)carbonyl diimidazole according to Staab H. A. and G. Walther (Ann., 1962, 657, 104-107), for example: 
This compound reacts readily with a suitably substituted ortho-aminobenzyl alcohol XII to give a hydroxy(thio)urea XIII (R=H) which is readily cyclized in aqueous strong acid medium to the compound of formula I which is the subject of the present invention, as described in patent application WO 97/05314: 
By N-alkylation of I (R=H) with an alkyl halide after sodation with NaH, the compound I in which R=alkyl is similarly prepared.
When R is other than a hydrogen, the activation of the amine X is carried out with thiophosgene or triphosgene to give a (thio)carbamoyl chloride XTV in an aprotic solvent in basic medium. 
This derivative is not isolated, but is added directly to the o-aminobenzyl alcohol XII to give the corresponding hydroxy(thio)urea XIII which is cyclized by the same process as above:
When they are not commercially available, the aminobenzyl alcohols XII are prepared by reducing the suitably substituted corresponding anthranilic esters.
The aminopiperidines X are prepared by adapting the process described in the base patent WO 97/05314 by N-alkylation of the protected 4-piperidones XV with the corresponding halo ethers III, followed by a deprotection of the compound obtained, to give the keto amine XVI which undergoes a reductive amination with the amine Rxe2x80x94NH2 (XVII) in the presence of borane-pyridine or sodium borohydride triacetate according to the scheme: 